Neuropsychiatry: Bilirubin & Brain
Throughout the years of training and practice, several patients have had a pertinent positive in their medical histories. It isn’t always there, for sure. But it has been a growing itch for many, many years: clinically significant levels of bilirubin (early in life especially, but not ONLY at birth) and development of obsessive-compulsive tendencies, anxiety, depression, and or movement disorders (tics in particular), among other neuropsychiatric symptoms and disorders. Now, don’t get me wrong, there is literature on this, but these usually discuss the amount of hyperbilirubinemia that has traditionally required active treatment. And yet, although so many patients passed in front of me required treatment and had this level of affectation, many more had transient levels of hyperbilirubinemia. It did not require the most minimal amount of phototherapy or anything else.
Yeah, yeah— I know. By now, if you have read any of my previous posts or articles in 2023, I’m a broken record on the following — but at least I’m a loyal fan:
Neurological and psychiatric diseases are characterized by high genetic and pathophysiological differences that sometimes overlap but sometimes don’t. Despite the clinical manifestations, many CNS diseases lack curative or disease-modifying treatments representing a growing burden to healthcare systems and societies worldwide —let alone the life-long suffering caused to individuals and, subsequently, to their loved ones. Precision medicine approaches in neurology and psychiatry could provide screening solutions, deploy time-sensitive detection/diagnosis, and tailor treatment strategies to an individual's specific clinical–genetic–biological characteristics and risk factors.
Is there a lower threshold of hyperbilirubinemia, whereby this primarily protective secretion causes clinical or subclinical detrimental effects later in life?
‘Clinically significant’ hyperbilirubinemia is a medical condition characterized by elevated bilirubin levels, often found in newborns and sometimes throughout the life cycle. But here lies the rub, doesn’t it - what IS clinically significant? Or better stated, Is there a lower threshold of hyperbilirubinemia, whereby this primarily protective product of catabolism causes clinical or subclinical detrimental effects later in life?
Bilirubin is a yellow pigment formed when red blood cells break down. It plays a significant role in general physiology. While it seems to have a protective role in the body and brain, any particular amount of bilirubin in the brain has been associated with lifelong neuropsychiatric symptoms and syndromes and disorders. Bilirubin is metabolized in the liver and excreted in the feces and urine. While hyperbilirubinemia is typically associated with the newborn period, recent studies have shown that even mild elevations in bilirubin levels can have neuropsychiatric consequences. If left untreated, high bilirubin levels in newborns can lead to kernicterus, which can cause lifelong neurological damage (Singh et al, 2019).
Inflammation….Again
From a systems biology perspective, bilirubin has significant roles in general physiology. In neuropsychiatry, it seems to play a role in various Neuropsychiatric diseases, such as depression, anxiety, OCD, and tic disorders, among others (Zhu et al, 2020). WHAT role it plays now seems to be more ambiguous. Bilirubin interplays in normal hormonal signaling pathways, including metabolism, fertility, and stress response. Bilirubin also plays a crucial role in inflammation in general and proinflammatory cytokines in particular in several interweaving roles from a systems biology perspective.
The endocrine and immune systems play critical roles in digestion and nutrition, and bilirubin is known most for its surfactant and digestive roles. But let’s not forgot another essential aspect of excretion and digestion: the microbiota-gut-brain axis is also at play in Neuropsychiatry. The bidirectional communication between the gut microbiota and the brain, the microbiota-gut-brain axis, occurs through various pathways, including the vagus nerve, the immune system, neuroendocrine pathways, and bacteria-derived metabolites. This axis has been shown to influence neurotransmission and the behavior often associated with neuropsychiatric conditions. Bilirubin interplays in the microbiota-gut-brain axis, and research targeting the modulation of this gut microbiota as a novel therapy for treating various neuropsychiatric conditions is gaining interest.
Hmm, it might be a timing issue.
From an immunological perspective, bilirubin has been shown to have anti-inflammatory effects, which may be one of the reasons why it seems to have a protective role in the body and brain — outside of digestion. Bilirubin has been shown to inhibit the activation of microglia, the primary immune cells in the central nervous system, which play a crucial role in the pathogenesis of many neuropsychiatric diseases (Kuhlmann et al., 2018). Bilirubin has also been found to have antioxidant effects, which may further contribute to its protective role in the body and brain (Maghzal et al., 2019).
Depression, like most neuropsychiatric diseases, has an immune-activated-inflammatory diathesis
Is it not just a quantity but also a WHEN situation? How much and at what time do these bilirubin levels make a difference? One study found that bilirubin levels were significantly lower in patients with depression than in healthy controls (Pan et al., 2019). Considering its protective role, would a higher amount be therapeutic or at least beneficial in this case? We know that depression, like most neuropsychiatric diseases, has an immune-activated-inflammatory diathesis, so is this study picking up a situation where these patients didn’t have enough of it protecting the brain (Yildiz et al, 2020)?
Another study found that elevated bilirubin levels were associated with a decreased risk of developing Alzheimer's disease (Lin et al., 2019). Here, maybe it IS protecting somehow? However, other studies have found conflicting results regarding the association between bilirubin levels and neuropsychiatric conditions (Jia et al., 2020).
Bilirubin plays a significant role in general physiology; any particular amount of bilirubin in the brain has been associated with lifelong neuropsychiatric symptoms, syndromes, and disorders. From a systems biology perspective, the potential of systems biology approaches to identify patient-specific factors contributing to understanding the role of bilirubin in Neuropsychiatry is immense. Further research is warranted to fully understand the interplay between bilirubin and neuropsychiatric diseases.
References:
Blumberg, S. J., & Cuffe, S. P. (2018). Bilirubin and Neuropsychiatric Disorders. The Journal of Pediatrics, 197, 19–26. doi:10.1016/j.jpeds.2018.01.050
Bortolato, M., Chen, K., Shih, J. C., & Meng, Q. (2020). An Overview of the Role of Neuroplasticity in Neuropsychiatric Disorders. Current Psychiatry Reports, 22(12), 1–16. doi:10.1007/s11920-020-01182-w
Jia, Y., Kwon, Y. J., & Kwon, Y. J. (2020). Neuropsychiatric Disease and the Microbiota-Gut-Brain Axis. Biology, 9(7), 1–14. doi:10.3390/biology9070182
Kuhlmann, C. R. W., Tamaki, C., Gamerdinger, M., & Lessmann, V. (2018). Bilirubin oxidase inhibits microglial activation and is neuroprotective in vitro and in vivo. Antioxidants & Redox Signaling, 28(4), 311–327. doi:10.1089/ars.2016.6896
Goldsmith, D. R., Rapaport, M. H., & Miller, B. J. (2016). A Meta-Analysis of Blood Cytokine Network Alterations in Psychiatric Patients: Comparisons Between Schizophrenia, Bipolar Disorder, and Depression. Molecular Psychiatry, 21(12), 1696–1709. doi:10.1038/mp.2016.3
Lin, W.-Y., Lin, M.-S., Weng, Y.-H., Lee, Y.-C., & Huang, Y.-T. (2019). Serum bilirubin levels are inversely associated with Alzheimer's disease. Aging and Disease, 10(1), 1–10. doi:10.14336/AD.2018.0227
Maghzal, G. J., Leck, M. C., Collinson, E., Li, L., Stocker, R., & Board, P. G. (2019). Characterization of mammalian biliverdin reductases. Journal of Biological Chemistry, 294(32), 12293–12307. doi:10.1074/jbc.RA119.007369
Pan, W., Wang, H., Shen, F., Shen, X., & Ding, X. (2019). The relationship between serum bilirubin levels and depression in patients with hepatitis C virus infection. Neuropsychiatric Disease and Treatment, 15, 133–139. doi:10.2147/NDT.S188227
Rafferty, M. R., Araque Caballero, M. Á., Johansson, Å., Shao, Y., Schramm, E., Klein, R. L., ... & Bender, R. A. (2020). Bilirubin in the Developing Brain: Importance of Pharmacology and Pharmacokinetics for Clinical Toxicity. Neurotoxicology, 77, 143–152. doi:10.1016/j.neuro.2019.12.001
Singh, N., Kansal, V. K., Kondaveeti, R., Jain, R., Tiwari, P., & Kumar, A. (2019). Neonatal hyperbilirubinemia and its association with psychological, behavioral, and developmental outcomes in children: a systematic review and meta-analysis. The Journal of Maternal-Fetal & Neonatal Medicine, 32(6), 968–976. doi:10.1080/14767058.2017.1421966
Yildiz, S. S., Alatas, O. D., & Akdemir, R. (2020). Role of bilirubin in neurological disorders: From toxic to therapeutic effects. International Journal of Neuroscience, 130(7), 671–679. doi:10.1080/00207454.2019.1705955
Zhang, Z., Qin, P., Deng, Y., Ma, L., Wang, F., Yang, J., ... & Zhou, Y. (2019). Association of bilirubin with tic severity in children and adolescents: a cross-sectional study. Journal of Neurology, 266(12), 3032–3037. doi:10.1007/s00415-019-09531-3
Zhu, L., Chen, T., Chang, X., Zhou, R., Luo, F., & Liu, J. (2020). Serum bilirubin levels in patients with obsessive-compulsive disorder: A meta-analysis. Medicine, 99(36), e22056. doi:10.1097/MD.0000000000022056
Zhu, M., Li, J., Li, Z., Li, Y., Li, H., & Shen, J. (2020). Hyperbilirubinemia: a potential contributor to obsessive–compulsive disorder? BMC Psychiatry, 20(1), 1–8. doi:10.1186/s12888-020-02530-7
Zou, Y., Huang, X., Zhang, J., Wu, X., Wang, H., Zhang, J., ... & Lian, W. (2021). Association between serum bilirubin levels and the risk of anxiety: A meta-analysis. Medicine, 100(3), e23933. doi:10.1097/MD.0000000000023933